Cancer and virus chemotherapy are the major theme of the on- going studies in this laboratory. Antimetabolites, such as nucleoside and folate analogs, and compounds which interfere with the activity of DNA metabolizing enzymes are the primary compounds of interest. The overall aims of our studies are not only to develop new compounds but also to modify the use of those compounds in current clinical use. In order to achieve these goals, efforts were made in this laboratory to identify the potential targets for the development of new compounds, to understand the metabolism and the mechanism to action of those compounds which are currently used, or potentially useful in clinics, and to examine the development and mechanism of cell resistance to those clinically useful compounds. The scope of studies involve purification and characterization of human enzymes involved in DNA metabolism, design and synthesis of enzyme inhibitors, mechanism of anticancer and antiviral drug action, mechanism of cell or virus resistance to anticancer or antiviral compounds, new clinical protocal design, identification of targets and design of strategies for developing antiherpes virus and anti HIV compounds, and diagnosis or prognosis of herpes virus associated diseases. Future research plans are to examine the "auto-regulatory" hypothesis in terms of the regulation of enzyme synthesis in order to provide leads in designing a new class of drugs, to study the "transient multiple drug resistance", to develop strategies in preventing the development of "permanent" drug resistant cells due to target enzyme amplification, to establish the rational basis for selecting or developing collaterally sensitive compounds to drug resistant cells, to study DNA metabolizing enzymes from human cells and virus infected cells and the development of anticancer and antiviral compounds. All those projects are interrelated and a consolidation of the research projects under this application will offer the stability of research and should facilitate the progress of those projects.